Core-shell structured upconversion nanocrystal-dendrimer composite as a carrier for mitochondria targeting and catalase enhanced anti-cancer photodynamic therapy.

Recently, photodynamic therapy (PDT) has been deemed to be the most promising strategy for cancer treatment. To improve the efficacy for PDT, nanocarriers are expected to target mitochondria that are vulnerable to toxic reactive oxygen species (ROS). Moreover, overcoming tumor hypoxia is also conducive to enhance the PDT efficacy. Upconversion nanoparticles (UCNPs) can convert near infrared (NIR) light to visible light, thus stimulating photosensitizers to effectively produce cytotoxic ROS and achieving a high tissue penetration depth. In this study, a multifunctional nanocarrier UCNPs@G4/Ce6/CAT-CTPP was synthesized by a novel thiol-ene and azide-acetylene click reaction route to connect the original oleic acid ligands and dendrimers. Interestingly, the constructed "hydrophobic and hydrophilic pockets" around one single upconversion nanoparticle can simultaneously load hydrophobic photosensitizer Chlorin e6 (Ce6) and hydrophilic catalase (CTA) for catalytic enhanced PDT activated by NIR laser. Also, the mitochondrial targeting molecules (3-carboxypropyl) triphenylphosphonium bromide (CTPP) were modified outside of the dendrimers to efficiently target mitochondria. Both the catalytic degradation of hydrogen peroxide (H2O2) by catalase to overcome tumor hypoxia and mitochondrial targeting greatly enhance the efficacy of PDT. More importantly, this system provides a new paradigm for designing inorganic nanocrystal core and dendrimer shell for cargo delivery.

MnFe2O4-decorated large-pore mesoporous silica-coated upconversion nanoparticles for near-infrared light-induced and O2 self-sufficient photodynamic therapy.

The limited light penetration depth and tumor hypoxia are two natural shortcomings of photodynamic therapy (PDT). Overcoming these two issues within a single system is still a great challenge. Herein, photosensitizer (PS)-loaded and PEG-modified MnFe2O4-decorated large-pore mesoporous silica-coated ß-NaYF4:20%Yb,2%Er@ß-NaYF4 upconversion nanoparticles (UCMnFe-PS-PEG) as excellent PDT agents are successfully prepared for NIR light-mediated and O2 self-sufficient PDT. The large mesoporous structure observably increases PS loading efficiency (11.33 wt%) and the green luminescence from upconversion nanoparticles activated by NIR is able to activate PSs to generate ROS effectively. In addition, sub-10 nm MnFe2O4 nanoparticles work as a Fenton catalyst to generate O2in situ. In vivo experiments further prove that UCMnFe-PS-PEG not only provides magnetic guidance to the tumor, but also overcomes tumor hypoxia and dramatically enhances PDT efficiency. Furthermore, in vivo MR and UCL imaging are performed for accurate cancer therapy. We believe that the successful construction of the multifunctional UCMnFe-PS-PEG provides more revelations for developing advanced nano-drug systems for cancer therapy.

Intelligent Hollow Pt-CuS Janus Architecture for Synergistic Catalysis-Enhanced Sonodynamic and Photothermal Cancer Therapy.

As a noninvasive treatment modality, ultrasound (US)-triggered sonodynamic therapy (SDT) shows broad and promising applications to overcome the drawbacks of traditional photodynamic therapy (PDT) in combating cancer. However, the SDT efficacy is still not satisfactory without oxygen (O2) assistance. In addition, there is also much space to explore the SDT-based synergistic therapeutic modalities. Herein, a novel Pt-CuS Janus composed of hollow semiconductor CuS and noble metallic Pt was rationally designed and successfully synthesized. The hollow CuS shows a large inner cavity for loading sonosensitizer molecules (tetra-(4-aminophenyl) porphyrin, TAPP) to implement SDT. Moreover, the deposition of Pt not only enhances photothermal performance compared with those of CuS nanoparticles (NPs) due to the effect of the local electric field enhancement but also possesses nanozyme activity for catalyzing decomposition of endogenous overexpressed hydrogen peroxide (H2O2) to produce O2 that can overcome tumor hypoxia and augment the SDT-induced highly toxic reactive oxygen species (ROS) production for efficient cancer cell apoptosis. Importantly, the generated heat of Pt-CuS by 808 nm laser irradiation can accelerate the catalytic activity of Pt and elevate the O2 level that further facilitates SDT efficacy. Interestingly, the thermally sensitive copolymer coated around the Janus can act as a smart switch to regulate the catalytic ability of Pt and control TAPP release that has a significant effect on modulating the therapeutic effect. The synergistic catalysis-enhanced SDT efficiency and highly photothermal effect almost realized complete tumor resection without obvious reoccurrence and simultaneously displayed a highly therapeutic biosafety. Furthermore, the high optical absorbance allows the as-synthesized Pt-CuS Janus for photoacoustic (PA) imaging and NIR thermal imaging. This work develops a versatile nanoplatform for a multifunctional theranostic strategy and broadens the biological applications by rationally designing their structure.

Facile Fabrication of Nanoscale Porphyrinic Covalent Organic Polymers for Combined Photodynamic and Photothermal Cancer Therapy.

Photodynamic therapy (PDT) of cancers is usually inefficient due to the relatively low level of oxygen in cancer cells; therefore, it needs to combine with other treatment strategies such as chemotherapy or photothermal therapy (PTT) to achieve the best anticancer efficacy. Although porphyrin-containing materials have been widely studied for PDT, the photothermal effect is rarely reported. Herein, nanoscale porphyrin-containing covalent organic polymers (PCOPs) were produced via a room temperature solution-based aging method. The resulting nanoparticles possess high photothermal conversion efficiency (21.7%) and excellent photodynamic effect. For the first time, the in vitro and in vivo tests indicated an enhanced antitumor efficacy for PCOP with combined PDT and PTT. This study provides an efficient approach to fabricate nanoCOP and also demonstrates the great potential of porphyrin-containing COP for biomedical applications.

Postsynthetic Ligand Exchange of Metal-Organic Framework for Photodynamic Therapy.

Attributed to the large pore size and excellent stability, the metal-organic framework (MOF), NU-1000, which is formed by the coordination of Zr cluster and 1,3,6,8-tetrakis( p-benzoic acid)pyrene (H4TBAPy) ligand, has been widely studied in the catalysis research field; however, only a few reports about the biomedical application of NU-1000 could be found in the open literature. In this study, a functional ligand, tetrakis(4-carboxyphenyl)porphyrin (TCPP), was introduced into NU-1000 via a postsynthetic ligand exchange method and the resulting mixed ligand MOF has an excellent photodynamic effect. Finally, in vitro and in vivo assessment about the antitumor efficacy was investigated for the first time. It demonstrates the feasibility of TCPP-substituted NU-1000 to be used for photodynamic therapy and also provides an alternative approach to enrich the function of MOF for various applications via a postsynthetic method.

Honeycomb-Satellite Structured pH/H2O2-Responsive Degradable Nanoplatform for Efficient Photodynamic Therapy and Multimodal Imaging.

The oxygen-deprived environment of a solid tumor is still great restriction in achieving an efficient photodynamic therapy (PDT). In this work, we developed a smart pH-controllable and H2O2-responsive nanoplatform with degradable property, which was based on honeycomb manganese oxide (hMnO2) nanospheres loaded with Ce6-sensitized core-shell-shell structured up-conversion nanoparticles (NaGdF4:Yb/Er,Tm@NaGdF4:Yb@NaNdF4:Yb) (abbreviated as hMUC). In the system, the speedy breakup of the as-prepared hMnO2 nanostructures results in release of loaded Ce6-sensitized UCNPs under the condition of H2O2 in acid solution. When exposed to tissue-penetrable 808 nm laser, up-conversion nanoparticles (UCNPs) emit higher-energy visible photons which would be absorbed by Ce6 to yield cytotoxic reactive oxygen species (ROS), thus triggering PDT treatment naturally. Moreover, the in vitro and in vivo experiments demonstrate that hMUC sample with the honeycomb-satellite structure can serve as multimodal bioimaging contrast agent for self-enhanced upconversion luminescence (UCL), magnetic resonance imaging (MRI) and computed tomography (CT) imaging, indicating that the as-prepared hMUC could be used in imaging-guided diagnosis and treatment, which has a potential application in the PDT treatment of tumor.

Facile preparation of ion-doped poly(p-phenylenediamine) nanoparticles for photothermal therapy.

Ion-doped poly(p-phenylenediamine) (Fe-ppd) nanoparticles were prepared at room temperature by using FeCl3 as an oxidant. Fe-ppd exhibited high photothermal conversion efficiency (39.27%) and excellent photostability. In vitro and in vivo evaluation demonstrated that Fe-ppd could be used as an ideal photothermal agent for photothermal therapy for the first time.

A novel core-shell structured upconversion nanorod as a multimodal bioimaging and photothermal ablation agent for cancer theranostics.

A multifunctional core-shell nanocomposite based on noble metal plasmons coated with upconversion material has emerged as a promising cancer theranostics nanoplatform that integrates properties such as multimodal imaging, photothermal effects, good biocompatibility, and efficient therapy. However, a reasonable combination of plasmons and upconversion materials, as well as increased penetration depth, has always challenged the anti-cancer efficiency. Here, a unique kind of fluorescent thermal-magnetic resonance core-shell upconversion nanostructure has been designed and fabricated to simultaneously achieve photothermal therapy (PTT) and multimodal imaging. Gold nanorods (GNRs) are used as the plasmon cores and NaGdF4 with rare-earth Yb3+/Er3+ ions co-doping are used as the upconversion luminescence (UCL) shells, merging into upconversion nanorods (UCNRs) of GNRs@NaGdF4:Yb3+,Er3+. An NaGdF4 shell synthesized by a hydrothermal method can substitute for the cetyltrimethylammonium bromide (CTAB) on the surface of GNRs, which offers the benefits of reducing toxicity and increasing biocompatibility. More significantly, the red and green emission of Yb3+/Er3+ couples convert near-infrared (NIR) into visible light, appropriately overlapping with absorbance of GNRs, which improves the photothermal conversion efficiency. Meanwhile, we designed small and low-aspect-ratio GNR cores for the absorption of UCNRs in vivo. Verification with evidence from in vivo and in vitro assays shows that these core-shell UCNRs exhibit a talented potential application in multimodal bioimaging and PTT.